Adamts13 compositions and methods for treating and diagnosing complications of coronavirus disease

Abstract

Provided herein are methods and compositions for treating a coronavirus disease, and particularly its complications, in a subject infected with a pathogenic coronavirus, such as a subject infected with a SARS-CoV-2 or suffering from one or more signs or symptoms of COVID-19. The composition comprises a therapeutically effective amount of an isolated or recombinant disintegrin and metalloproteinase with a thrombospondin type 1 motif (ADAMTS13) protein. The present disclosure further relates to methods for diagnosing a coagulopathy in subject infected with a coronavirus disease, particularly SARS-CoV-2, or suffering from one or more signs or symptoms of COVID-19. The method comprises testing for elevated levels of VWF, depressed levels of ADAMTS13, and the presence of UHMW VWF multimers. These factors, in combination, indicate the presence of a coagulopathy.

What is claimed is: 
     
         1 . A method of treating or preventing at least one condition or complication in a subject infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or suffering from coronavirus disease 2019 (COVID-19), the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition comprising A disintegrin and metalloproteinase with a thrombospondin type 1 motif (ADAMTS13). 
     
     
         2 . A method of treating a subject at risk of developing at least one condition or complication associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (COVID-19), the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition comprising A disintegrin and metalloproteinase with a thrombospondin type 1 motif (ADAMTS13). 
     
     
         3 . A method of treating or preventing at least one condition or complication in a subject infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or suffering from coronavirus disease 2019 (COVID-19), comprising the steps of:
 a) administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a recombinant A Disintegrin And Metalloproteinase with Thrombospondin type 1 motif, member-13 (ADAMTS13), wherein said therapeutically effective amount is sufficient to:
 i) reduce circulating ultra-high molecular weight (UHMW) von Willebrand factor (VWF) multimers to a level that is at least about 5%, at least about 10%, or at least about 20% decreased compared to a measured level of VWF in the subject's blood prior to administration; 
 ii) reduce circulating UHMW VWF multimers to a level that is no more than about 5%, no more than about 10%, or no more than about 20% above a normal VWF baseline value; 
 iii) reduce circulating VWF to a level that is at least about 5%, at least about 10%, or at least about 20% decreased compared to a measured level of VWF in the subject's blood prior to administration; 
 iv) reduce circulating VWF to a level that is no more than about 5%, no more than about 10%, or no more than about 20% above a normal VWF baseline value; 
 v) reduce VWF activity level to a level that is at least about 5%, at least about 10%, or at least about 20% decreased compared to a measured level of VWF activity in the subject's blood prior to administration; 
 vi) reduce VWF activity level to a level that is no more than about 5%, no more than about 10%, or no more than about 20% above a normal VWF activity baseline value; 
 vii) increase circulating ADAMTS13 levels from about 100% to about 150% above a normal ADAMTS13 baseline value; or 
 viii) combinations of i)-vii); and 
   b) periodically monitoring and adjusting the administered amount to maintain said reduced level of circulating VWF, UHMW VWF multimers, or combinations thereof.   
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the subject is administered the composition comprising ADAMTS13 before the condition or complication is present. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the subject is administered the composition comprising ADAMTS13 after the condition or complication is present. 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the condition or complication is a coagulopathy, blood-clotting disorder, infarction, thrombosis, embolism, stroke, veno-occlusive disorders, prothrombotic conditions, sepsis, renal failure, respiratory failure, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), thrombotic microangiopathy (TMA), pneumonia, asthma, hypertension, elevated plasma levels of VWF and/or its multimers (especially ultralarge multimers (UHMW)), elevated plasma VWF activity levels, reduced plasma levels of endogenous ADAMTS13, inflammation, elevated cytokine levels, or combination thereof. 
     
     
         7 . The method of  claim 6 , wherein the thrombosis is deep vein thrombosis (DVT). 
     
     
         8 . The method of  claim 6 , wherein the embolism is a pulmonary embolism (PE). 
     
     
         9 . The method of  claim 6 , wherein the complication is elevated plasma levels of VWF, elevated plasma levels of UHMW VWF multimers, and/or reduced plasma levels of endogenous ADAMTS13. 
     
     
         10 . The method of any one of  claims 1 - 9 , wherein the subject is 65 years of age or older. 
     
     
         11 . The method of any one of  claims 1 - 10 , wherein the subject presents with a risk factor. 
     
     
         12 . The method of  claim 11 , wherein the risk factor is elevated plasma levels of VWF, elevated plasma levels of ultralarge multimers (UHMW) VWF multimers, elevated plasma VWF activity levels, reduced plasma levels of endogenous ADAMTS13, reduced activity of endogenous ADAMTS13 activity, elevated cytokine levels, coagulopathies, blood-clotting disorders, veno-occlusive disorders, prothrombotic conditions, inherited thrombotic thrombocytopenic purpura (TTP), acquired TTP, disseminated intravascular coagulation (DIC), sepsis, sickle cell, respiratory failure, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), thrombotic microangiopathy (TMA), pneumonia, asthma, pregnancy, menopause, pen-menopause, hypertension, pulmonary hypertension, thromboses, embolism, myocardial infarction, stroke, cough, shortness of breath, pulmonary infiltrates, respiratory failure, elevated plasma fibrogen, activated hemostasis pathway, intensive care unit (ICU) admission, or combinations thereof. 
     
     
         13 . The method of  claim 12 , wherein the risk factor is a elevated plasma levels of VWF, elevated plasma levels of UHMW VWF multimers, and/or reduced plasma level of endogenous ADAMTS13. 
     
     
         14 . The method of  claim 12 , wherein the risk factor is a prothrombotic condition. 
     
     
         15 . The method of any one of  claims 1 - 14 , wherein administering the composition comprising ADAMTS13 to the subject reduces the duration, severity, or frequency of occurrence of the condition or complication compared to a subject that was not administered the composition comprising ADAMTS13; b) reduces plasma level of VWF protein, plasma level of VWF multimers, VWF activity, plasma ratio of VWF to ADAMTS13 (VWF:A13), platelet aggregation, blood clotting, thrombosis, embolism, infarction, veno-occlusion, stroke, inflammation, plasma cytokine levels, or combinations thereof as compared to a normal baseline range in a healthy individual; c) reduces plasma level of VWF protein, plasma level of VWF multimers, VWF activity, plasma VWF:A13, or combinations thereof; d) reduces platelet aggregation, blood clotting, thrombosis, embolism, infarction, veno-occlusion, stroke, or combinations thereof; e) increases plasma levels of ADAMTS13, plasma ADAMTS13 activity, or combinations thereof to a normal baseline range in a healthy individual; or f) a combination of a)-e). 
     
     
         16 . The method of  claim 15 , wherein the VWF multimer is an UHMW multimer. 
     
     
         17 . The method of any one of  claims 1 - 16 , wherein administering the composition comprising ADAMTS13 to the subject increases plasma level of ADAMTS13, plasma ADAMTS13 activity, or combinations thereof from about 20-100%, above a normal baseline range or normal baseline value of ADAMTS13 plasma level or ADAMTS13 activity level. 
     
     
         18 . The method of any one of  claims 1 - 17 , wherein administering the composition comprising ADAMTS13 to the subject increases plasma level of ADAMTS13, plasma ADAMTS13 activity, or combinations thereof from about 100-150%, compared to a normal baseline value of ADAMTS13 plasma level or ADAMTS13 activity level. 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein the therapeutically effective amount of the ADAMTS13 is about 10-400 IU/kg for a subject having a VWF level that is more than about 5% higher than a baseline corresponding to the upper limit of a predetermined normal range of VWF levels in healthy subjects. 
     
     
         20 . The method of any one of  claims 1 - 19 , wherein the therapeutically effective amount of the ADAMTS13 is about 10-400 IU/kg or about 40-400 IU/kg for a subject having a VWF level that is at least about two times higher than a normal baseline VWF level in healthy subjects. 
     
     
         21 . The method of any one of  claims 1 - 18 , wherein the therapeutically effective amount of the ADAMTS13 is about 10-400 IU/kg or about 40-400 IU/kg for a subject having a VWF level that is at least about three times higher than a normal baseline VWF level in healthy subjects. 
     
     
         22 . The method of any one of  claims 1 - 18 , wherein the therapeutically effective amount of the ADAMTS13 is about 10-400 IU/kg for a subject having an ADAMTS13 activity and/or level between about 30-70% that of a normal ADAMTS13 baseline activity and/or level in healthy subjects. 
     
     
         23 . The method of any one of  claims 1 - 18 , wherein the therapeutically effective amount of the ADAMTS13 is about 10-400 IU/kg or about 40-400 IU/kg for a subject having an ADAMTS13 activity and/or level less than about 20% of a normal ADAMTS13 baseline activity and/or level in healthy subjects. 
     
     
         24 . The method of any one of  claims 1 - 18 , wherein the therapeutically effective amount of the ADAMTS13 is about 10-400 IU/kg or about 40-400 IU/kg for a subject having a ultra-high molecular weight (UHMW) VWF multimer level between about 100-130% that of a normal UHMW VWF multimer baseline level in healthy subjects. 
     
     
         25 . The method of any one of  claims 1 - 18 , wherein the therapeutically effective amount of the ADAMTS13 is about 10-400 IU/kg for a subject having a ultra-high molecular weight (UHMW) VWF multimer level at least about 101%, at least about 105%, or at least about 107% that of a normal UHMW VWF multimer baseline level in healthy subjects. 
     
     
         26 . The method of any one of  claims 1 - 25 , wherein the therapeutically effective amount of the ADAMTS13 is about 10-320 IU/kg, about 10-300 IU/kg, about 10-200 IU/kg, about 10-180 IU/kg, about 10-160 IU/kg, about 10-80 IU/kg, about 10-60 IU/kg, about 10-40 IU/kg, about 10-20 IU/kg, about 20-320 IU/kg, about 20-300 IU/kg, about 20-200 IU/kg, about 20-180 IU/kg, about 20-160 IU/kg, about 20-80 IU/kg, about 20-60 IU/kg, about 20-40 IU/kg, or about 20-30 IU/kg, about 30-320 IU/kg, about 30-300 IU/kg, about 30-180 IU/kg, about 30-160 IU/kg, about 30-60 IU/kg, about 40-400 IU/kg, about 40-320 IU/kg, about 40-300 IU/kg, about 40-180 IU/kg, about 40-160 IU/kg, about 40-80 IU/kg or about 40-60 IU/kg. 
     
     
         27 . The method of any one of  claims 1 - 25 , wherein the therapeutically effective amount of the ADAMTS13 is about 10-40 IU/kg, about 10-20 IU/kg, about 40-320 IU/kg, about 40-160 IU/kg, about 40-80 IU/kg, or about 40-60 IU/kg. 
     
     
         28 . The method of any one of  claims 1 - 27 , wherein the composition comprising ADAMTS13 is administered monthly, every two weeks, weekly, twice a week, three times a week, every other day, daily, every 12 hours, every 8 hours, every six hours, every four hours, every two hours, or every hour. 
     
     
         29 . The method of any one of  claims 1 - 27 , wherein the composition comprising ADAMTS13 is administered intravenously, subcutaneously, via intravenous bolus, or via intravenous infusion. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein the composition comprising ADAMTS13 comprises plasma derived human ADAMTS13. 
     
     
         31 . The method of any one of  claims 1 - 29 , wherein the composition comprising ADAMTS13 comprises recombinant ADAMTS13. 
     
     
         32 . The method of any one of  claims 1 - 31 , comprising the further steps of:
 periodically measuring the subject's VWF level; and   reducing the therapeutically effective amount to about 10-100 IU/kg when the subject's VWF level is within a predetermined baseline range of a healthy individual.   
     
     
         33 . The method of any one of  claims 15 - 32 , wherein a normal baseline range for VWF levels is a range of about 50-200% or about 42-136% of an established or predetermined average baseline. 
     
     
         34 . The method of any one of  claims 15 - 33 , wherein a normal baseline range for ADAMTS13 levels is a range of about 40-160% or about 87-113% of an established or predetermined average baseline. 
     
     
         35 . A method of determining whether a subject diagnosed with COVID-19 is at an increased risk for a thrombotic coagulopathy, said method comprising the steps of:
 a) measuring in a blood plasma sample one or more of:
 i) a plasma level of VWF protein; 
 ii) an activity level of VWF in the plasma sample; 
 iii) a plasma level of UHMW VWF protein multimers; 
 iv) a plasma level of ADAMTS13 protein; or 
 v) an activity level of ADAMTS13 protein in the plasma sample; and 
   b) comparing the plasma level(s) or activity level(s) measured in step a) to a baseline range or baseline value for the same plasma level(s) or activity level(s); and   c) identifying the subject being at risk for a thrombotic coagulopathy when at least one of the following is met:
 i) the plasma level of VWF protein is increased; 
 ii) the activity level of VWF is increased; 
 iii) plasma UHMW VWF protein multimers are detected or the plasma level of UHMW VWF protein multimers is increased; 
 iv) the plasma level of ADAMTS13 protein is decreased; or 
 v) the activity level of ADAMTS13 protein is decreased, 
   as compared to the baseline range or baseline value for the same plasma level(s) or activity level(s).   
     
     
         36 . The method of  claim 35 , wherein thrombotic coagulopathy includes platelet aggregation, blood clotting, a thrombosis, a thrombotic microangiopathy, an embolism, an infarction, veno-occlusion, a stroke, renal failure resulting from thrombosis, or combinations thereof. 
     
     
         37 . The method  claim 35  or  claim 36 , wherein the subject is at risk for developing a thrombotic coagulopathy when the plasma level of VWF protein is about 120% to about 300% of the baseline value for said VWF protein plasma level. 
     
     
         38 . The method of any one of  claims 35 - 37 , wherein the subject is at risk for developing a thrombotic coagulopathy when the plasma level of VWF protein is about 300% or more of the baseline value for said VWF protein plasma level. 
     
     
         39 . The method of any one of  claims 35 - 38 , wherein the subject is at risk for developing a thrombotic coagulopathy when the activity level of VWF in the plasma sample is about 120% to about 300% of the baseline value for said VWF activity level. 
     
     
         40 . The method of any one of  claims 35 - 39 , wherein the subject is at risk for developing a thrombotic coagulopathy when the activity level of VWF in the plasma sample is about 300% or more of the baseline value for said VWF activity level. 
     
     
         41 . The method of any one of  claims 35 - 40 , wherein the subject is at risk for developing a thrombotic coagulopathy when the plasma level of ADAMTS13 protein is about 70% to about 100% of the baseline value for said ADAMTS13 protein plasma level. 
     
     
         42 . The method of any one of  claims 35 - 41 , wherein the subject is at risk for developing a thrombotic coagulopathy when the plasma level of ADAMTS13 protein is 70% or less of the baseline value for said ADAMTS13 protein plasma level. 
     
     
         43 . The method of any one of  claims 35 - 42 , wherein the subject is at risk for developing a thrombotic coagulopathy when the activity level of ADAMTS13 in the plasma sample is about 70% to about 100% of the baseline value for said ADAMTS13 activity level. 
     
     
         44 . The method of any one of  claims 35 - 43 , wherein the subject is at risk for developing a thrombotic coagulopathy when the activity level of ADAMTS13 in the plasma sample is 70% or less of the baseline value for said ADAMTS13 activity level. 
     
     
         45 . The method of any one of  claims 35 - 44 , wherein the subject is at risk for developing a thrombotic coagulopathy when the plasma level of UHMW VWF multimers is about 100% to about 110% of the baseline value for said UHMW VWF multimer plasma level. 
     
     
         46 . The method of any one of  claims 35 - 45 , wherein the subject is at risk for developing a thrombotic coagulopathy when the plasma level of UHMW VWF multimers is 110% or more of the baseline value for said UHMW VWF multimer plasma level. 
     
     
         47 . The method of any one of  claims 35 - 46 , wherein the subject is at risk for developing a thrombotic coagulopathy when the ratio of VWF:A13 levels in the plasma sample is 3 or less. 
     
     
         48 . The method of any one of  claims 35 - 47 , wherein the subject is at risk for developing a thrombotic coagulopathy when the ratio of VWF:A13 levels in the plasma sample is greater than 3. 
     
     
         49 . The method of any one of  claims 35 - 48 , wherein the baseline value is a predetermine value based on a normal control population. 
     
     
         50 . The method any one of  claims 35 - 49 , wherein the baseline value is a mean of a predetermine range of a normal control population. 
     
     
         51 . A method of determining whether a subject diagnosed with COVID-19 is at risk for a thrombotic coagulopathy, said method comprising the steps of:
 a) measuring in a blood plasma sample one or more of:
 i) a plasma level of VWF protein; 
 ii) an activity level of VWF in the plasma sample; 
 iii) a plasma level of UHMW VWF protein multimers; 
 iv) a plasma level of ADAMTS13 protein; or 
 v) an activity level of ADAMTS13 protein in the plasma sample; and 
   b) identifying the subject being at risk for a thrombotic coagulopathy when at least one of the following is met:
 i) the plasma level of VWF protein is at least about 1.2 IU/ml; 
 ii) the VWF activity level is at least about 1.2 IU/ml or 1.8 IU/ml; 
 iii) plasma UHMW VWF protein multimers are detected; 
 iv) the plasma level of ADAMTS13 protein no more than about 0.7 IU/ml; or 
 v) the activity level of ADAMTS13 protein is no more than about 0.8 or about 0.9 IU/ml. 
   
     
     
         52 . The method of  claim 51 , wherein in step b) the subject is at a high risk for a thrombotic coagulopathy when at least one of the following is met:
 i) the plasma level of VWF protein is at least about 4.5 IU/ml;   ii) the VWF activity level is at least about 3.3 IU/ml or 4.4 IU/ml;   iii) the plasma level of ADAMTS13 protein no more than about 0.4 IU/ml; or   iv) the activity level of ADAMTS13 protein is no more than about 0.4 or about 0.5 IU/ml.   
     
     
         53 . The method of any one of  claims 35 - 52 , wherein the method further comprises administering to the subject a composition comprising a therapeutically effective amount of ADAMTS13. 
     
     
         54 . The method of  claim 53 , wherein the therapeutically effective amount of the ADAMTS13 is about 10-400 IU/kg, about 10-320 IU/kg, about 10-300 IU/kg, about 10-200 IU/kg, about 10-180 IU/kg, about 10-160 IU/kg, about 10-80 IU/kg, about 10-60 IU/kg, about 10-40 IU/kg, about 10-20 IU/kg, about 20-320 IU/kg, about 20-300 IU/kg, about 20-200 IU/kg, about 20-180 IU/kg, about 20-160 IU/kg, about 20-80 IU/kg, about 20-60 IU/kg, about 20-40 IU/kg, about 20-30 IU/kg, about 30-320 IU/kg, about 30-300 IU/kg, about 30-180 IU/kg, about 30-160 IU/kg, about 30-60 IU/kg, about 40-400 IU/kg, about 40-320 IU/kg, about 40-300 IU/kg, about 40-180 IU/kg, about 40-160 IU/kg, about 40-80 IU/kg or about 40-60 IU/kg. 
     
     
         55 . The method of any one of  claim 37 ,  39 ,  41 ,  43 ,  45 ,  47 , or  51 , wherein the method further comprises administering to the subject a composition comprising a therapeutically effective amount of ADAMTS13 and wherein the therapeutically effective amount of the ADAMTS13 is about 10-40 IU/kg, about 10-30 IU/kg, about 10-20 IU/kg, about 20-40 IU/kg, or about 20-30 IU/kg. 
     
     
         56 . The method of  claim 55 , wherein the therapeutically effective amount of the ADAMTS13 is about 10 IU/kg, about 20 IU/kg, about 30 IU/kg, or about 40 IU/kg. 
     
     
         57 . The method of any one of  claim 38 ,  40 ,  42 ,  44 ,  46 ,  48 , or  52 , wherein the method further comprises administering to the subject a composition comprising a therapeutically effective amount of ADAMTS13 and wherein the therapeutically effective amount of the ADAMTS13 is about 40-400 IU/kg, about 40-320 IU/kg, about 40-300 IU/kg, about 40-180 IU/kg, about 40-160 IU/kg, about 40-80 IU/kg or about 40-60 IU/kg. 
     
     
         58 . The method of  claim 57 , wherein the therapeutically effective amount of the ADAMTS13 is about 40 IU/kg, about 60 IU/kg, about 80 IU/kg, or about 160 IU/kg. 
     
     
         59 . A kit for determining whether a subject diagnosed with COVID-19 is at risk for a thrombotic coagulopathy, said kit comprising (i) one or more reagents for determining one or more of the plasma level of VWF protein, activity level of VWF, plasma level of UHMW VWF multimers, plasma level of ADAMTS13 protein, activity level of ADAMTS13, (ii) optionally packaging and/or instructions for use, and (iii) optionally one or more reagents for detecting SARS-CoV-2 or diagnosing COVID-19.